期刊
DIABETES
卷 50, 期 10, 页码 2363-2375出版社
AMER DIABETES ASSOC
DOI: 10.2337/diabetes.50.10.2363
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资金
- NHLBI NIH HHS [HL-43023, HL-39902, HL-66923, HL-65573, HL-65577, HL-38132] Funding Source: Medline
- NIA NIH HHS [AG-17042, AG-15756] Funding Source: Medline
To determine whether enzymatic p53 glycosylation leads to angiotensin II formation followed by p53 phosphorylation, prolonged activation of the renin-angiotensin system, and apoptosis, ventricular myocytes were exposed to levels of glucose mimicking diabetic hyperglycemia. At a high glucose concentration, O-glycosylation of p53 occurred between 10 and 20 min, reached its peak at 1 It, and then decreased with time. Angiotensin II synthesis increased at 45 min and I h, resulting in p38 mitogen-activated protein (MAP) kinase-driven p53 phosphorylation at Ser 390. p53 phosphorylation was absent at the early time points, becoming evident at 1 h, and increasing progressively from 3 It to 4 days. Phosphorylated p53 at Ser 18 and activated c-Jun NH2-terminal kinases were identified with hyperglycemia, whereas extracellular signal-regulated kinase was not phosphorylated. Upregulation of p53 was associated with an accumulation of angiotensinogen and AT(1) and enhanced production of angiotensin II. Bax quantity also increased. These multiple adaptations paralleled the concentrations of glucose in the medium and the duration of the culture. Myocyte death by apoptosis directly correlated with glucose and angiotensin II levels. Inhibition of O-glycosylation prevented the initial synthesis of angiotensin II, p53, and p38-MAP kinase (MAPK) phosphorylation and apoptosis. AT(1) blockade had no influence on O-glycosylation of p53, but it interfered with p53 phosphorylation; losartan also prevented phosphorylation of p38-MAPK by angiotensin II. Inhibition of p38-MAPK mimicked at a more distal level the consequences of losartan. In conclusion, these in vitro results support; the notion that hyperglycemia with diabetes promotes myocyte apoptosis mediated by activation of p53 and effector responses involving the local renin-angiotensin system.
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